Comprehensive structural and functional characterization of Mycobacterium tuberculosis UDP-NAG enolpyruvyl transferase (Mtb-MurA) and prediction of its accurate binding affinities with inhibitors

Abstract

Tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death in the world. One third of the world's population is infected with Mycobacterium tuberculosis (Mtb), the etiologic agent of TB. The bacterial enzyme MurA catalyzes the transfer of enolpyruvate from phosphoenolpyruvate (PEP) to uridine diphospho-N-acetylglucosamine (UNAG), which is the first committed step of bacterial cell wall biosynthesis. In this work, 3D structure model of Mtb-MurA enzyme has been developed for the first time by homology modeling and molecular dynamics simulation techniques. Multiple sequence alignment and 3D structure model provided the putative substrate binding pocket of Mtb-MurA with respect to E. coli MurA. This analysis was helpful in identifying the binding sites and molecular function of the MurA homologue. Molecular docking study was performed on this 3D structure model, using different classes of inhibitors like fosfomycin, cyclic disulfide analog RWJ-3981, pyrazolopyrimidine analog RWJ-110192, purine analog RWJ-140998, 5-sulfonoxy-anthranilic acid derivatives T6361, T6362 and the results showed that the 5-sulfonoxyanthranilic acid derivatives showed the best interaction compared to other inhibitors. We also designed new efficient analogs of T6361 and T6362 which showed even better interaction with Mtb-MurA than the parental 5-sulfonoxy-anthranilic acid derivatives. Further the comparative molecular electrostatic potential and cavity depth analysis of Mtb-MurA suggested several important differences in its substrate and inhibitor binding pocket. Such differences could be exploited in the future for designing a more specific inhibitor for Mtb-MurA enzyme.

Cell wall peptidoglycan inMycobacterium tuberculosis: An Achilles’ heel for the TB-causing pathogen

“…Homology modelling, molecular dynamics and molecular docking studies on the mycobacterial MurA and MurB enzymes revealed active site residues and helped identifying potential inhibitors (Babajan et al . 2011; Kumar et al . 2011).…”

sncRNA-1 Is a Small Noncoding RNA Produced by Mycobacterium tuberculosis in Infected Cells That Positively Regulates Genes Coupled to Oleic Acid Biosynthesis

“…There are additional sncRNA-6 homologous sequences that are 19 nt in length, and lack 2 nt in the 3′ end of the mature sncRNA-6 (data not shown). sncRNA-8 is located between murA and rrs (16s RNA), with murA involved in cell wall formation ( Figure 1F ) ( Babajan et al, 2011 ). Whether the sncRNAs present at multiple loci were expressed from each location has not been evaluated.…”

Computed insight into a peptide inhibitor preventing the induced fit mechanism of MurA enzyme from Pseudomonas aeruginosa

“…Thus, a gap in residues Pro64, Ile65, and Ala151 was employed to build the model. The modeled active site of MurA includes many residues found in MurA enzymes of other species . The key catalytic residue Cys115 is conserved (Cys117 in MurA‐ PA ).…”